As a result of experiences with nicotine, some people become regular users, others develop a pattern of intermittent use, and still others avoid the substance entirely. Because sensitivity to nicotine's effects (which includes rewarding as well as avervise consequences) determines the initial reinforcement context for self-administration, sensitivity sets the stage for subsequent nicotine use. The long-term, objective of the proposed research is to elucidate the relationships between sensitivity to nicotine and the development of tolerance in order to gain a better understanding of nicotine dependence and susceptibility to cigarette smoking. The specific aims are to use challenge-doses of nicotine aerosol as a probe to explore individual differences in sensitivity to nicotine and the development of tolerance, using subjective/hedonic, physiological, and hormonal responses as markers. The research design involves within- and between-group comparisons of smokers and non-smokers in a sequence of four Experiments over 5 years. In Experiments I and II, changes in reactivity to a challenge-dose of nicotine will be determined over 11 days of abstinence, in order to explore the relationships among pharmacodynamic sensitivity to nicotine, nicotine intake (from a usual cigarette), and dependence in regular smokers. In Experiments III, never-smokers, occasional smokers ('chipper"), ex-smokers, and regular smokers will be exposed to several challenge dose levels of nicotine, in an attempt to define the basic parameters of pharmacokinetics sensitivity to nicotine in subjects with markedly different histories of nicotine use. In Experiment IV, two challenge doses of nicotine will be administered 120 minutes apart, in order to determine the development of tolerance in the above-mentioned groups. Among the health implications of the proposed research is that it may provide the basis for a more comprehensive understanding of organism/environment interactions in the genesis of smoking, and it could lead to the development of methods to assess susceptibility to nicotine before smoking and nicotine dependence have become entrained; the research could also provide new perspectives from which to evaluate the strengths and weakness of current methods for prevention and treatment of smoking.